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PARP inhibitor

Tuesday 6 November 2012

PARP inhibitors

WKP

PARP is a protein thati s involved in DNA repair. PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). They are developed for multiple indications; the most important is the treatment of cancer.

Several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for cancer therapy.

In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases.

Mechanism of action

DNA is damaged thousands of times during each cell cycle, and that damage must be repaired. BRCA1, BRCA2 and PALB2 are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombinational repair, or HRR, pathway.

When the gene for either protein is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. When subjected to enough damage at one time, the altered gene can cause the death of the cells.

PARP1 is a protein that is important for repairing single-strand breaks (’nicks’ in the DNA). If such nicks persist unrepaired until DNA is replicated (which must precede cell division), then the replication itself can cause double strand breaks to form.

Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2 mutations these double strand breaks cannot be efficiently repaired, leading to the death of the cells.

Normal cells that don’t replicate their DNA as often as cancer cells, and that lacks any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP.

Some cancer cells that lack the tumor suppressor PTEN may be sensitive to PARP inhibitors because of downregulation of Rad51, a critical homologous recombination component, although other data suggest PTEN may not regulate Rad51.

Hence PARP inhibitors may be effective against many PTEN-defective tumours (e.g. some aggressive prostate cancers).

Cancer cells that are low in oxygen (e.g. in fast growing tumors) are sensitive to PARP inhibitors.

Examples

Started Phase III

- Iniparib (BSI 201) for breast cancer and squamous cell lung cancer. Failed trial for triple negative breast cancer.

Started Phase II

- Olaparib (AZD-2281) for breast, ovarian and colorectal cancer. AZ not progressing it to phase III.
- Rucaparib (AG014699, PF-01367338) for metastatic breast and ovarian cancer.
- Veliparib (ABT-888) for metastatic melanoma and breast cancer.
- CEP 9722 for non–small-cell lung cancer (NSCLC)

Started Phase I

- MK 4827 Inhibitor of PARP1 and PARP2. Phase I trial on 59 patients.
- BMN-673 in trials for advanced hematological malignancies and for advanced or recurrent solid tumors.

Experimental

- 3-aminobenzamide, a prototypical PARP inhibitor

Combination with radiotherapy

The main function of radiotherapy is to produce DNA strand breaks, causing severe DNA damage and leading to cell death.

Radiotherapy has the potential to kill 100% of any targeted cells, but the dose required to do so would cause unacceptable side effects to healthy tissue.

Radiotherapy therefore can only be given up to a certain level of radiation exposure.

Combining radiation therapy with PARP inhibitors offers promise, since the inhibitors would lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue with BRCA1/BRCA2 mutations.

This combination could therefore lead to either more powerful therapy with the same radiation dose or similarly powerful therapy with a lower radiation dose.